How to break the cycle of gut inflammation, dysbiosis, and epithelial energy starvation

Originally published in 2019, this remains one of the most important articles I’ve ever written. It was updated in 2025 to reflect the latest research—much of which has only strengthened its core message.

Virtually every cell in the human body requires oxygen. That is – every human cell. Most of our microbial companions, however, thrive in environments devoid of oxygen. When oxygen leaks into the gut, it disrupts this balance, promoting inflammation and microbial imbalances. In this article, I explore the oxygen-gut dysbiosis connection in depth, with a look at how cellular energy metabolism supports gut barrier integrity, microbial balance, and overall homeostasis. I’ll also share how various interventions, including butyrate and creatine, might be harnessed to help break the cycle.

The healthy colon: a low oxygen environment rich in microbes

The gut is home to a dense microbial community. The healthy human colon contains an estimated 38 trillion bacterial cells, most of which are obligate anaerobes—bacteria that thrive only in low-oxygen environments. Many of these bacteria are essential for breaking down complex carbohydrates into short-chain fatty acids (SCFAs) like butyrate.

The colon also hosts a small number of facultative anaerobes, which can grow with or without oxygen. These include many gut pathogens. In a healthy gut, the low oxygen concentration and dominance of obligate anaerobes suppress the growth of these facultative species.

Butyrate helps maintain “physiologic hypoxia” in the colon

One of the important metabolites produced by obligate anaerobes is the short-chain fatty acid (SCFA) butyrate, a fermentation product of dietary fiber.

In the healthy gut, butyrate supplies about 70 percent of the energy used by colonocytes, the cells that line the colon and form the gut barrier. These cells metabolize butyrate via mitochondrial beta-oxidation, which consumes a large amount of oxygen. This oxygen consumption helps create a hypoxic (low-oxygen) state within the gut epithelium.

In 2015, a research group led by Dr. Sean Colgan at the University of Colorado demonstrated that gut metabolism of butyrate was required for maintaining “physiologic hypoxia” in the colon.² Through a series of experiments, they demonstrated that butyrate, and to a lesser extent, the SCFAs propionate and acetate, deplete oxygen levels in colonocytes. This leads to the stabilization of a protein called hypoxia-inducible factor (HIF), which acts as a sort of “oxygen sensor” in the cell. When oxygen levels are low, HIF promotes the expression of genes that help coordinate gut barrier protection. If oxygen levels rise, HIF is no longer stabilized, and these gut-protective genes are no longer expressed.

The researchers wondered whether antibiotics could affect this state of hypoxia. After just three days of broad-spectrum antibiotics, butyrate levels had dropped dramatically, gut oxygen levels had risen, and the state of epithelial hypoxia was lost. The oxygen-sensor HIF was no longer stabilized, and the gut-protective genes were no longer expressed, leading to a loss of gut barrier function.

And it wasn’t just for lack of fiber, the substrate for butyrate production. The gut microbiota of the antibiotic-treated mice had completely lost its ability to produce butyrate or other SCFAs from dietary fermentable fibers! Fortunately, they went on to find that the administration of supplemental butyrate was able to rescue the “physiologic hypoxia” and gut barrier function. But more on that later.

A microbial signature of gut dysbiosis: low abundance of butyrate producers and an expansion of facultative anaerobes

The term “gut dysbiosis” generally refers to an altered state of the gut microbiota, often associated with disease. In the last decade, advanced sequencing techniques have allowed us to characterize gut dysbiosis in hundreds of different diseases. While there are countless microbial patterns that could be considered dysbiotic, a few consistent trends emerge.

As Litvak et al. wrote in a 2017 review:

“Perhaps the most consistent and robust ecological pattern observed during gut dysbiosis is an expansion of facultative anaerobic bacteria belonging to the phylum Proteobacteria.” ³

Proteobacteria is one of the five major bacterial phyla in the human gut— Escherichia, Shigella, Salmonella, Helicobacter, Vibrio, Yersinia, Pseudomonas, Campylobacter, and Desulfovibrio—many of which are considered opportunistic pathogens. These microbes are generally harmless at low abundance but can become problematic when the gut environment shifts in their favor.

One environmental factor that leads to a rapid expansion of Proteobacteria is oxygen leakage. Most Proteobacteria are facultative anaerobes, meaning they can survive and reproduce in the presence of oxygen. This gives them a significant advantage over beneficial obligate anaerobes when oxygen levels rise.

Notably, the expansion of Proteobacteria is almost always accompanied by a decline in butyrate-producing bacteria – a microbial signature of dysbiosis. This pattern has been linked to numerous chronic conditions, including:

• Inflammatory bowel disease⁴
• Irritable bowel syndrome⁵
• Colorectal cancer⁶
• Diverticulitis⁷
• Histamine intolerance⁸
• Type 2 diabetes⁹
• Obesity¹⁰

As we’ll see in the next section, this microbial signature often reflects a deeper issue: epithelial metabolic dysfunction.

Epithelial cell metabolism drives gut dysbiosis

Epithelial cells line the gut wall and serve as the primary interface between host and microbes. Recall from earlier that in a healthy gut, colonocytes primarily metabolize fatty acids like butyrate using mitochondrial beta-oxidation – a process that consumes significant oxygen. This oxygen use maintains a hypoxic (low-oxygen) state in the gut, supporting a microbiota dominated by obligate anaerobes.

These obligate anaerobes, in turn, ferment fiber into SCFAs like butyrate, which are absorbed and used as fuel by colonocytes. This creates a positive feedback loop that reinforces gut homeostasis.

However, when colonocyte metabolism is disrupted —whether due to antibiotics, inflammation, or other stressors—this loop breaks down. Energy-starved colonocytes must look for other sources of energy. They switch away from fatty acid oxidation and begin utilizing glucose from the bloodstream instead. This shift to anaerobic glycolysis consumes little oxygen and results in the production of lactate.¹¹

At the same time, inflammation ramps up production of nitrate. Without the usual oxygen demand, excess oxygen, lactate, and nitrate begin to leak into the gut lumen.

This new environment—richer in oxygen and alternative electron acceptors—gives a competitive edge to facultative anaerobic pathogens like Salmonella, Klebsiella, Citrobacter, and E. coli—which can tolerate oxygen and thrive on lactate and nitrate. Meanwhile, beneficial obligate anaerobes, including key butyrate-producers, are suppressed by the oxygenation of the gut.

In short: “The metabolism of colonocytes functions as a control switch of the gut microbiota, mediating a shift between homeostatic and dysbiotic communities.” ¹¹

So, what causes epithelial cells to make this switch that ultimately leads to gut dysbiosis? Next, we’ll explore the common disruptors that trigger this metabolic switch—including antibiotics, infections, and low-fiber diets.

Antibiotics deplete colonic butyrate and drive oxygen leakage into the gut

Last spring, I had the pleasure of meeting Dr. Sebastian Winter, a professor of microbiology and immunology at UT Southwestern—and one of the few researchers deeply exploring the connection between epithelial metabolism and host-microbe interactions.

In an 2016 animal study, Dr. Winter’s lab demonstrated that a single dose of streptomycin resulted in a fourfold reduction in gut butyrate levels.¹² This was primarily due to the depletion of Clostridia—a class of bacteria that includes many key butyrate-producers, like Eubacterium, Roseburia, Butyrivibrio, Clostridium, Coprococcus, and Ruminococcus.

Using a special staining technique, they showed that antibiotic treatment increased oxygenation in colonocytes and disrupted mucosal hypoxia. As a result, oxygen leaked into the gut lumen, allowing oxygen-tolerant pathogens like Salmonella to expand rapidly.

It’s worth noting that streptomycin was chosen precisely because of its strong impact on Clostridia—making it ideal for studying the effects of butyrate depletion. It’s not commonly used orally in humans. However, many broad-spectrum antibiotics are known to impact butyrate-producing bacteria, suggesting that a 1–2 week course of other antibiotics may cause a similar breakdown in epithelial metabolism and oxygen balance.

Pathogenic bacteria can hack colonocyte metabolism to promote gut dysbiosis

Certain pathogens may also exploit the colonocyte metabolic switch to gain a competitive advantage in the gut. If you’ve ever had a bout of food poisoning and struggled with gut symptoms long after the acute infection resolved, this may help explain why.

In the same 2016 paper from Dr. Winter’s lab, Byndloss et al. demonstrated that certain strains of Salmonella (specifically Salmonella enterica serotype Typhimurium, hereafter abbreviated S. Tm) can manipulate the host epithelium to promote gut dysbiosis.¹²

S. Tm is a particularly virulent bacterium that invades the intestinal mucosa, triggering severe inflammation. This inflammation depletes butyrate-producing Clostridia—further enhancing S. Tm‘s ability to thrive in the gut.

In other words, S. Tm appears to “hack” host metabolism: it induces inflammation, reduces butyrate, and alters the gut environment in ways that suppress healthy microbes while promoting its own growth.

Interestingly, the loss of Clostridia in this case was more gradual than with antibiotics—occurring over 1–3 weeks—and was much slower to recover. Even four weeks after infection, Clostridia abundance remained over two orders of magnitude below baseline.

In addition, the inflammation induced by S. Tm led to the release of reactive oxygen and nitrogen species, which reacted with simple sugars to form substrates that selectively fed S. Tm and other members of the Enterobacteriaceae family (Proteobacteria).

This isn’t unique to S. Tm. In 2007, Lupp et al. showed that Citrobacter rodentium and Campylobacter jejuni infections also triggered intestinal inflammation and promoted Enterobacteriaceae overgrowth.¹³

Altogether, this suggests that gut infections can oxygenate the colon and drive prolonged dysbiosis. Clearing these infections may be a key step in restoring epithelial metabolism and microbial balance.

A low-fiber diet may drive oxygen leakage and Proteobacteria expansion

We’ve now seen how antibiotic use and gut infections can deplete butyrate, leading to oxygen leakage and dysbiosis. But there’s another, much more common factor that may trigger the same cascade: a low-fiber diet.

Since the primary source of butyrate is dietary fiber, inadequate intake can significantly reduce butyrate production. When butyrate is lacking, colonocytes don’t get the fuel they need for mitochondrial respiration. Instead, they shift to anaerobic glucose metabolism, which consumes much less oxygen. As a result, oxygen begins to leak into the gut.

While this mechanism hasn’t yet been as thoroughly demonstrated in low-fiber models as it has for antibiotics and infection, multiple studies link low fiber intake to increased levels of Proteobacteria:

• A large comparative study of children in Europe and rural Burkina Faso found that European children had significantly higher levels of Enterobacteriaceae.¹⁴ The researchers speculated that this was due to the low fiber content in the Western diet.
• A 2009 study found that individuals on a gluten-free diet had reduced levels of Bifidobacterium and Lactobacillus, alongside an increase in Enterobacteriaceae. The gluten-free diet had significantly lowered the participants’ intake of polysaccharides.

What about a low-carb, ketogenic diet? As I’ve written previously, ketone bodies like acetoacetate and beta-hydroxybutyrate can serve as alternative fuels for gut epithelial cells. For this reason, it’s unlikely that a well-formulated ketogenic diet would trigger this same oxygen leakage mechanism. In fact, ketones may actually help restore epithelial hypoxia. (But more on that later.)

Other agents that contribute to gut inflammation may also drive gut dysbiosis

Intriguingly, all of the factors we’ve covered so far—antibiotics, infections, and low-fiber diets—not only reduce butyrate but also increase intestinal inflammation. This raises an important point: inflammation itself can promote dysbiosis.

In 2007, Lupp et al. showed that gut inflammation alone—whether triggered chemically (via dextran sodium sulfate, DSS) or genetically (via IL-10 knockout mice)—was enough to disrupt microbial balance and drive overgrowth of Enterobacteriaceae.¹³

More subtle inflammatory agents may also fuel dysbiosis. For example:

• Chassaing et al. (2015) found that feeding mice the emulsifiers carboxymethylcellulose and polysorbate-80 for 12 weeks reduced microbial diversity and increased mucosa-associated Proteobacteria.¹⁵
• Palmnäs et al. showed that rats given the non-caloric sweetener aspartame for 8 weeks had increased Enterobacteriaceae.¹⁶

Stress can also play a role. Langgartner et al. reported a rise in Proteobacteria in a mouse model of chronic psychosocial stress.¹⁷ And while more research is needed, unrecognized food intolerances may similarly promote inflammation, impair colonocyte metabolism, and drive dysbiosis.

Altogether, these findings reinforce a core idea: anything that inflames the gut or disrupts epithelial metabolism has the potential to oxygenate the colon and tip the microbiome toward dysbiosis.

Alright, so we’ve reviewed several things that can cause gut hypoxia and drive gut dysbiosis. For the remainder of this article, I want to focus on things we can do to potentially interrupt this cycle and restore gut homeostasis. First up: butyrate!

Butyrate helps maintain gut hypoxia and protects against pathogen expansion after antibiotics

Since publishing my article on why probiotics might not be the best choice after antibiotics, I’ve received a lot of questions about what can be done to support gut health during and after antibiotic treatment.

At the time, I didn’t have a great answer. Now, having dug deeper into the research, I now believe there’s a strong case for butyrate supplementation—especially in the context of antibiotic use. Over the next few sections, I’ll lay out the research that supports this hypothesis, and close with my recommendations for putting this into action.

Let’s return to Dr. Winter’s research. As mentioned earlier, streptomycin treatment depleted butyrate-producing microbes and led to oxygenation of the gut mucosa. But here’s the key finding: when mice were given oral tributyrin (a gut-targeted form of butyrate), epithelial hypoxia was restored, and cecal butyrate levels significantly increased.¹²

This effect extended to infection models as well. In mice infected with S. Typhimurium after streptomycin treatment, tributyrin supplementation reduced the pathogen’s competitive advantage. Without butyrate, S. Tm rapidly expanded in the gut. But when tributyrin was provided just three hours post-infection, that advantage disappeared.

This finding suggests that restoring epithelial energy metabolism with butyrate can directly limit the expansion of facultative pathogens—even in a post-antibiotic environment.

Butyrate restores hypoxia and protects against C. difficile-induced colitis

In 2019, Fachi et al. demonstrated in a mouse model that butyrate supplementation during antibiotic treatment could reduce the severity of colitis caused by Clostridioides difficile.¹⁸

Clostridioides difficile (previously classified as Clostridium difficile and commonly abbreviated C. diff) is a gram-positive, spore-forming bacterium that is a common cause of intestinal infection after antibiotic use.

In this study, mice received butyrate starting one day before antibiotics and continuing through the infection challenge. Interestingly, butyrate did not reduce C. diff colonization or toxin production, but it did stabilize HIF-1, enhance gut barrier integrity, and significantly reduce inflammation and bacterial translocation.

The researchers tested two additional strategies for increasing butyrate levels:

• High-dose tributyrin given during the three days surrounding infection
• A high-fiber diet (containing a whopping 25% inulin) started after antibiotics but before infection

Both were equally protective, further supporting the idea that epithelial energy metabolism—not just direct microbial killing—is central to gut resilience.

So clearly, butyrate protects against pathogen expansion after antibiotics. But can butyrate prevent the full spectrum of dysbiosis associated with antibiotics, by supporting colonocyte metabolism? This remains to be determined in controlled studies, but as we’ll see in the next section, the pieces certainly seem to fit together nicely.

PPAR-gamma as the control switch for colonocyte metabolism

So far, I’ve referred to a metabolic “switch” in colonocytes that contributes to gut dysbiosis. It turns out this switch is largely mediated by a transcription factor called PPAR-gamma.

PPARs (peroxisome proliferator-activated receptors) are a group of proteins that regulate gene expression by binding to DNA. PPAR-gamma, in particular, is highly expressed in the colon and adipose tissue.

In a healthy gut, butyrate doesn’t just fuel colonocytes—it also activates PPAR-gamma, which enhances the cells’ ability to metabolize butyrate and other fatty acids. This creates a positive feedback loop: butyrate activates PPAR-gamma, which boosts fatty acid oxidation, consuming oxygen and reinforcing hypoxia. That hypoxic environment favors beneficial anaerobes and suppresses facultative pathogens.

In a dysbiotic gut, however, there is not enough butyrate or other substrates to activate PPAR-gamma. In turn, colonocytes shift to glycolysis and begin producing oxygen, lactate, and nitrate, which fuel the growth of pathogens.

Lower PPAR-gamma also drives up expression of Nos2, the gene that encodes inducible nitric oxide synthase (iNOS), contributing to nitrate accumulation—another competitive advantage for pathogens like E. coli and Salmonella.

But PPAR-gamma’s role doesn’t stop at metabolism. It also supports innate immune defenses. A 2010 study in PNAS showed that PPAR-gamma is needed to maintain expression of antimicrobial peptides like β-defensin, which regulates microbial colonization of the colon.¹⁹ Mice deficient in PPAR-gamma had impaired defenses against Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and E. coli. PPAR-gamma is also required for proper production of secretory IgA, a key component of gut mucosal immunity.²⁰

In short: PPAR-gamma is a central regulator of both colonocyte metabolism and gut immune defense—and represents a promising therapeutic target for restoring gut homeostasis.

Could stimulating the PPAR-gamma pathway prevent or reverse gut dysbiosis?

Several studies suggest that activating PPAR-gamma could be a promising strategy for preventing or reversing gut dysbiosis and intestinal injury.

For instance, PPAR-gamma expression is significantly reduced in inflammatory bowel disease (IBD).²¹ Medications that activate this pathway have shown significant therapeutic potential:

• Rosiglitazone, a thiazolidinedione drug that binds and activates PPAR-gamma, has been shown to prevent dysbiosis and reduce colitis symptoms in animal models when used acutely.²² While still used as an antidiabetic agent in the U.S., its side effects make it less suitable for long-term use.
• Mesalamine (5-ASA), a first-line IBD treatment, also activates PPAR-gamma—though to a more moderate degree. Because it acts locally in the gut, mesalamine carries fewer systemic side effects than rosiglitazone. Notably, its anti-inflammatory effects are mediated in part through PPAR-gamma activation.²³ Clinical studies show mesalamine reduces Proteobacteria and increases beneficial species like Faecalibacterium and Bifidobacterium.²⁴ More recent research has reinforced the importance of PPAR-gamma signaling in maintaining gut homeostasis. A 2024 study found that mesalamine—commonly used for IBD—can inhibit the expansion of dysbiotic E. coli by activating PPAR-gamma, lending further support to its microbiome-modulating effects.

Researchers are also investigating natural compounds that activate PPAR-gamma. For example, a team in Beijing identified a synthetic compound called Danshensu Bingpian Zhi (DBZ)—derived from components of the traditional Chinese formula Fufang Danshen—as a PPAR-gamma agonist. Although weaker than rosiglitazone, DBZ still provided significant protection against dysbiosis, gut barrier dysfunction, insulin resistance, and weight gain in a mouse model of diet-induced obesity.²⁵

There’s also evidence that butyrate itself activates PPAR-gamma. In a randomized, placebo-controlled trial of 49 patients with IBD, daily supplementation with 1800 mg of butyrate reduced inflammation, improved quality of life, and increased the abundance of butyrate-producing bacteria!²⁶

• In patients with Crohn’s disease, Butyricoccus and Subdoligranulum increased
• In ulcerative colitis, Lachnospiraceae became more dominant

While the researchers didn’t directly measure PPAR-gamma expression, the microbial and clinical shifts strongly suggest involvement of this pathway.

Altogether, this is an incredibly intriguing area of study that will no doubt get more attention in the years to come. As Litvak et al. wrote in their recent review published in the journal Science:

“Metabolic reprogramming of colonocytes to restore epithelial hypoxia represents a promising new therapeutic approach for rebalancing the colonic microbiota in a broad spectrum of human diseases.” ¹¹

In sum: stimulating PPAR-gamma—whether through pharmaceuticals, nutrients, or lifestyle—holds enormous potential for shifting the gut back toward homeostasis. More research is needed, but the therapeutic implications are exciting.

Strategies to target PPAR-gamma and support gut hypoxia

Below is a summary of interventions that may help activate PPAR-gamma in the gut and restore the hypoxic environment necessary for microbial balance. These strategies may be particularly useful in stubborn cases of dysbiosis, especially those marked by high Proteobacteria and low butyrate producers.

⚠️ Important: I write about these mechanisms for individuals who have already addressed foundational lifestyle habits but are still struggling with gut health. If you’re not yet sleeping well, eating a nutrient-dense diet, getting regular movement, or managing stress, start there.

This information is educational and not medical advice. Always consult your physician or gastroenterologist before beginning any new treatment, especially pharmaceutical or herbal interventions.

• Mesalamine (5-ASA): A standard first-line IBD medication. Its anti-inflammatory effects are mediated through PPAR-gamma activation.²³
• Danshensu Bingpian Zhi (DBZ): a compound derived from traditional Chinese medicine, shown in animal studies to activate PPAR-gamma and attenuate dysbiosis.²⁵ Note: Herbals should be sourced and dosed carefully, ideally under the direction of a physician experienced in herbal medicine.
• Butyrate: a short-chain fatty acid and potent stimulator of PPAR-gamma. Even low concentrations of butyrate have been shown to increase PPAR-gamma protein expression by 7-fold. I recommend delayed-release, colon-targeted forms like ProButyrate or Tributyrin-X (no affiliations).
• Ketones: beta-hydroxybutyrate and acetoacetate almost certainly activate PPAR-gamma in intestinal epithelial cells, just as butyrate does. A ketogenic diet has been shown to upregulate PPAR-gamma across a number of tissues and also provides substrate for beta-oxidation and epithelial energy production.
• Fasting/caloric restriction: One study found that intestinal PPAR-gamma was required for sympathetic nervous system activation during caloric restriction.²⁷ However, the degree to which fasting or caloric restriction induces this pathway in the gut is still unclear.
• Exercise: one research group found that the protective effects of voluntary exercise on the gut in both a colitis model and a diet-induced obesity model were mediated by the ability of exercise to increase endogenous glucocorticoids in the gut and upregulate PPAR-gamma!^28,29
• Stress management: stress reduces PPAR-gamma expression in the gut.²⁰
• Cannabinoids: cannabidiol (CBD) reduced iNOS activity in rectal biopsies of patients with ulcerative colitis, an effect that was mediated through activation of PPAR-gamma.³⁰
• Sulforaphane: a 2008 found that this phytochemical from cruciferous vegetables enhances components of innate immunity via activation of PPAR-gamma.³¹
• Curcumin: one study found that curcumin inhibited chemically-induced colitis in mice by activation of PPAR-gamma.³² The oral dosage required to achieve these effects is unknown.
• Other herbals: chamomile, angelica, silymarin, licorice root, and lemon balm are all partial activators of PPAR-gamma. These herbs can be taken individually but are all found within the product Iberogast, which has been shown to be clinically effective for IBS and functional GI disorders.³³
• Fatty acids: Conjugated linoleic acid (CLA)³⁴ and omega-3 fatty acids (DHA)³⁵ both enhance expression of PPAR-gamma.
• Probiotics: In vitro studies on colonocytes have demonstrated the ability of Saccharomyces boulardii to increase PPAR-gamma expression.
• Prebiotics: in vitro studies on colonocytes have shown that the anti-inflammatory effects of the oligosaccharides alpha3-siallylactose and FOS are mediated through their ability to induce PPAR-gamma.³⁶
• Vitamin A: retinoic acid, a form of vitamin A, is required for the activation and function of PPAR-gamma.

The importance of mitochondrial health

Mitochondria are central to butyrate metabolism and oxygen utilization in colonocytes. Without healthy mitochondria, even adequate butyrate may not be effectively used to maintain gut hypoxia and epithelial integrity.

In fact, PPAR-gamma activation itself supports mitochondrial health by promoting mitochondrial biogenesis—the process of creating new mitochondria. This helps colonocytes meet their high energy demands and maintain oxidative metabolism, which consumes oxygen and protects against dysbiosis.

That said, targeted mitochondrial support may offer additional benefits, especially in individuals with chronic inflammation, fatigue, or metabolic dysfunction.

Some key nutrients to consider:

• L-Carnitine – Facilitates the transport of fatty acids into mitochondria for beta-oxidation

• CoQ10 – Supports mitochondrial electron transport and ATP production

• Alpha-lipoic acid – A mitochondrial antioxidant that helps recycle other antioxidants and improve energy metabolism

Optimizing mitochondrial function may enhance the ability of colonocytes to use butyrate, ketones, or creatine efficiently—further supporting gut barrier health and microbial balance.

Harnessing synergy for breaking the cycle

While each of these interventions may be helpful on its own, their true power may lie in synergistic combinations that support gut health from multiple angles.

For example, mesalamine combined with curcumin or butyrate has been shown to be more effective for treating IBD than mesalamine alone.³⁷,³⁸ This suggests that integrating multiple, complementary therapies may enhance outcomes beyond what any one strategy can achieve.

Though the synergistic potential of combining more than two interventions hasn’t been thoroughly studied, it’s easy to imagine how an integrated approach could be more impactful. Consider a regimen that includes:

• Mesalamine, curcumin, and DHA to activate PPAR-gamma

• Butyrate and ketones to fuel epithelial energy metabolism

• L-carnitine to support mitochondrial uptake and utilization of those fuels

I am currently trialing such approaches in my one-on-one work with clients in collaboration with their gastroenterologists. Early observations are promising, but it will take time and structured data to understand the full potential.

Reminder: I am not a licensed physician and do NOT recommend using the more potent PPAR-gamma agonists without the close oversight of a medical doctor.

What about dysbiosis of the small intestine?

So far, we’ve focused primarily on colonic metabolism and dysbiosis. But we now know that small intestinal dysbiosis—rather than simple bacterial overgrowth—is a major driver of gut symptoms, particularly in conditions like irritable bowel syndrome (IBS).

As of this writing, the epithelial metabolic “switch” and oxygen leakage model has only been clearly demonstrated in the colon. That said, PPAR-gamma is also expressed in the small intestine (albeit at lower levels), and a similar mechanism may be at play.

In fact, a 2016 animal study published in PNAS found that a high-fat, high-sugar processed diet downregulated small intestinal PPAR-gamma nearly twofold.³⁹ This was associated with altered expression of antimicrobial genes and clear signs of small intestinal dysbiosis. When the mice were treated with rosiglitazone (a PPAR-gamma agonist) for one week, those effects were reversed.

We also know that glutamine, the preferred fuel source for small intestinal epithelial cells, can induce PPAR-gamma expression—similar to how butyrate works in the colon.⁴⁰,⁴¹ This makes glutamine a compelling candidate for supporting epithelial function in the small intestine.

What about mesalamine for IBS? Some studies have explored this off-label, with mixed results. Most found little benefit at standard doses. However, a recent trial using 1,500 mg once daily for 12 weeks showed significant improvements in patients with diarrhea-predominant IBS (IBS-D).⁴²

As with the colon, I believe that integrative, synergistic treatments hold promise for restoring small intestinal homeostasis. A combination of mesalamine or DBZ, glutamine, and ketones might be more effective than any of these alone—though clinical studies are needed to test this directly.

Regrettably, treatment of “SIBO” has largely focused on antibiotics, which may reduce symptoms in the short-term, but may further stress the gut epithelium, increasing the risk of relapse or worsening long-term symptoms. Rather than trying to “kill bacteria”, we need to shift our focus towards creating a gut environment that favors growth of healthy microbes.

Creatine: An emerging tool for gut epithelial energy and mitochondrial support

In addition to butyrate and glutamine—which fuel the colon and small intestine respectively—creatine has recently emerged as a valuable adjunct for supporting epithelial energy metabolism, particularly under conditions of stress or inflammation.

Well known for its role in muscle performance, creatine also plays a critical role in buffering ATP production, maintaining mitochondrial stability, and supporting cellular function in high-demand tissues—including the gut lining.

A 2021 study published in Gastroenterology found that intestinal epithelial cells rely on creatine to help maintain energy production and barrier integrity during stress. Cells with inadequate creatine shifted into a glycolysis-predominant, pro-inflammatory metabolic state, whereas creatine supplementation helped preserve oxidative metabolism and reduce metabolic stress.

This is particularly relevant in the context of dysbiosis, where mitochondrial function is often impaired, and energy-starved epithelial cells leak oxygen into the gut lumen—fueling inflammation and the expansion of Proteobacteria.

By helping epithelial cells meet their energy needs and maintain the low-oxygen environment that supports anaerobic microbes, creatine complements other metabolic supports like butyrate and glutamine. It may be especially helpful in protocols aimed at restoring gut homeostasis after antibiotic use, chronic inflammation, or persistent barrier dysfunction.

For a deeper dive into creatine’s expanding role in gut health, see my companion article: Creatine: It’s About Time We Talked About It for Gut Health.

Summary & takeaways: how this knowledge may inform treatment

That was a lot of information and nitty-gritty pathways, but hopefully you can see the enormous potential of this knowledge for shaping how we approach gut dysbiosis and disease! Here are the key takeaways from this body of research and potential ways to put this knowledge into practice:

1) High Proteobacteria and low butyrate-producers—a common signature of gut dysbiosis—typically indicates epithelial metabolic dysfunction and gut inflammation. This pattern can be seen on several commercially available microbiome tests.

2) Antibiotics, gut infections, low fiber intake, or stress can all deplete gut butyrate, lead to oxygen leakage into the gut, and promote gut dysbiosis. These factors reduce butyrate, impair colonocyte metabolism, and allow oxygen leakage into the gut—shifting the microbiota toward a dysbiotic, inflammatory state. Avoiding antibiotics whenever possible, treating existing gut infections, eating a nutrient-dense diet, and managing stress are key to supporting healthy gut metabolism and in turn, a healthy gut microbiota.

3) This new understanding of how oxygen drives gut dysbiosis directs future research and offers important insight as to how we might be able to reestablish a healthy ecosystem. If we can overcome the epithelial energy starvation and restore gut hypoxia, we may be able to restore a healthy gut ecosystem and reverse dysbiosis.

4) If you have to take antibiotics, take butyrate! Antibiotics wipe out butyrate producers, putting significant stress on the cells that line the large intestine. Supplemental butyrate can support the gut epithelium until our native butyrate-producers can recover by maintaining an environment that limits opportunistic pathogens. (Likewise, supplementing with glutamine may prevent antibiotic-induced dysbiosis in the small intestine.)

5) Creatine may be another overlooked but powerful tool. Creatine helps buffer cellular energy demands during stress, supports mitochondrial efficiency, and may preserve the low-oxygen gut environment that protects against dysbiosis. Consider it alongside butyrate and glutamine in energy-supportive gut protocols.

5) If basic diet and lifestyle interventions are not enough, targeting PPAR-gamma and colonic energy starvation may be key. This metabolic switch plays a central role in determining whether the gut supports health or inflammation. A combination of PPAR-gamma activators, energy substrates (butyrate, ketones, creatine), and mitochondrial nutrients may offer synergistic benefits, particularly for those with IBD or stubborn “SIBO”/IBS symptoms.

6) There are numerous interventions with the potential to synergistically “reprogram” colonocytes, ranging from drug therapies to nutrients and lifestyle factors. I discussed many of the known interventions in this article but am hopeful that future research will further explore these therapies, both in isolation and in combination, to elucidate the best therapies to treat gut dysbiosis.

That’s all for now! If you found this helpful, feel free to share your thoughts in the comments and subscribe for future updates. I’d also love to hear how this information has impacted your own gut health journey.